a) Field of the Invention
The invention relates to phosphonated derivatives of glycopeptide and lipoglycopeptide antibiotics. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
b) Brief Description of the Prior Art
Osteomyelitis is an inflammation of bone caused by a variety of microorganisms, mainly Staphylococcus aureus (Carek et al., American Family Physician (2001), Vol 12, 12:2413-2420). This painful and debilitating disease occurs more commonly in children. Within the adult population, diabetics and kidney dialysis patients are also vulnerable. The acute form of the disease is treatable with antibiotics, but requires a lengthy period of daily therapy. It can, however, revert to a recurrent or chronic form requiring repeated hospital stays and heavy treatment regimens.
Glycopeptide and lipoglycopeptide antibiotics are a class of biologically produced or semi-synthetic antimicrobial agents which affect the bacterial cell wall and/or membrane integrity (Williams, D. H et al, Angewandte Chemie International Edition in English (1999), 1999, 38; 1172-1193. Nicolaou, K. C. et al, Angewandte Chemie International Edition in English (1999), 38; 2097-2152. Kahne, D. et al Chemical Reviews (2005), 105; 425-448; Pace, J. L. et al, Biochemical Pharmacology (2006), 71; 968-980). Best known glycopeptide and lipoglycopeptide antibiotics are certainly vancomycin, teicoplanin, oritavancin (U.S. Pat. No. 5,840,684), dalbavancin (U.S. Pat. No. 5,750,509) and telavancin (U.S. Pat. No. 6,635,618). The two first drugs were proven clinically and microbiologically to have potent activity against gram-positive organisms and the latter three drugs are in clinical trials. Oritavancin, dalbavancin and telavancin possess extremely attractive pharmacological profiles with potent activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, intermediate and fully vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp. Although the use of highly active systemic anti-staphylococcal agents for the treatment of bone and joint infections is becoming attractive, results obtained in animal models using vancomycin or teicoplanin for the treatment of osteomyelitis have not been convincing (Luu, Q. N. et al, European Journal of Clinical Microbiology and Infectious Diseases (1989); 8; 562-563. Mader, J. T. et al Antimicrobial Agents and Chemotherapy (1989); 33; 689-692). The problem may be that although the drug are highly active, the actual intra-bone concentration of the drug is but a fraction of the systemic dose and therefore glycopeptide and lipoglycopeptide antibiotics could prove to be more effective if the proportion of the drug reaching the bone could be increased.
Bisphosphonates are well-characterized bone-seeking agents. These compounds are known to have a high affinity to the bones due to their ability to bind the Ca2+ ions found in the hydroxyapatite forming the bone tissues (Hirabayashi and Fujisaki, Clin. Pharmacokinet. (2003) 42(15): 1319-1330). Therefore, many different types of bisphosphonate-conjugated compounds have been made for targeting drugs selectively to the bone, including proteins (Uludag et al., Biotechnol Prog. (2000) 16:1115-1118), vitamins (U.S. Pat. No. 6,214,812 and WO 02/083150), tyrosine kinase inhibitors (WO 01/44258 and WO 01/44259), hormones (U.S. Pat. No. 5,183,815) and bone scanning agents (U.S. Pat. No. 4,810,486). These and other bisphosphonate derivatives have been used as therapeutic agents for bone diseases such as arthritis (U.S. Pat. No. 4,746,654), osteoporosis (U.S. Pat. No. 5,428,181 and U.S. Pat. No. 6,420,384), hypercalcemia (U.S. Pat. No. 4,973,576), and bone cancers (U.S. Pat. No. 6,548,042). Although some have suggested that bisphosphonate-antibiotics could also be made, only few of such compounds have actually being synthesized, including macrolides (U.S. Pat. No. 5,359,060), fluoroquinolones and β-lactams (U.S. Pat. No. 5,854,227; U.S. Pat. No. 5,880,111; DE 195 32 235; Pieper and Keppler, Phosphorus, Sulfur and Silicon (2001) 170:5-14; and Herczegh et al. J. Med. Chem (2002) 45:2338-41). Furthermore, prior to the present invention, no one has ever made or suggested to make phosphonated derivatives of glycopeptide or lipoglycopeptide antibiotics, nor suggested the use of such derivatives for the prevention or treatment of osteomyelitis.
In view of the above, there is a need for highly active antibiotics for the prevention and treatment of bone and joint infections. More particularly, there is a need for glycopeptide or lipoglycopeptide antibiotics with a higher affinity for bone, and a need for treatment methods wherein the intra-bone concentration of glycopeptide or lipoglycopeptide antibiotics is increased, for an extended period of time, above the minimal effective inhibitory concentrations which are required for killing bacteria.
The present invention fulfills these needs and also other needs as will be apparent to those skilled in the art upon reading the following specification.